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Inhibits T Cell Activation Capacity of Central Nervous System APCs1
Neuroinflammation Unit, Section for Immunology, Institute for Experimental Medical Science, Lund University, Lund, Sweden
We have previously investigated the physiological effects of IFN-
on chronic CNS inflammation and shown that IFN-–/– mice develop a more severe experimental autoimmune encephalomyelitis than their IFN-+/– littermates. This result was shown to be associated with a higher activation state of the glial cells and a higher T cell cytokine production in the CNS. Because this state suggested a down-regulatory effect of IFN- on CNS-specific APCs, these results were investigated further. We report that IFN- pretreatment of astrocytes and microglia (glial cells) indeed down-modulate their capacity to activate autoreactive Th1 cells. First, we investigated the intrinsic ability of glial cells as APCs and report that glial cells prevent autoreactive Th1 cells expansion while maintaining Ag-specific T cell effector functions. However, when the glial cells are treated with IFN- before coculture with T cells, the effector functions of T cells are impaired as IFN-
, TNF-
, and NO productions are decreased. Induction of the T cell activation marker, CD25 is also reduced. This suppression of T cell response is cell-cell dependent, but it is not dependent on a decrease in glial expression of MHC class II or costimulatory molecules. We propose that IFN- might exert its beneficial effects mainly by reducing the Ag-presenting capacity of CNS-specific APCs, which in turn inhibits the effector functions of encephalitogenic T cells. This affect is of importance because activation of encephalitogenic T cells within the CNS is a prerequisite for the development of a chronic progressive CNS inflammation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Swedish Foundation for Strategic Research, Swedish Research Council-Natural Science, Swedish Research Council-Medicine, Alfred Österlund Foundation, Tore Nilson Foundation, His Majesty Gustav V Foundation, the Royal Swedish Academy of Science, Royal Physiographic Society, Lund, Sweden, the M. Bergvalls Foundation, Åke Wiberg Foundation, Börje Dahlin Foundation, Segerfalk Foundation, and the Crafoord Foundation.
2 Address correspondence and reprint requests to Dr. Shohreh Issazadeh-Navikas, Neuroinflammation Unit, Institute for Experimental Medical Science, Biomedical Centre I13, Lund University, 221 84 Lund, Sweden. E-mail address: Shohreh.Issazadeh{at}med.lu.se
3 Abbreviations used in this paper: MS, multiple sclerosis; EAE, experimental autoimmune encephalomyelitis; MBP, myelin basic protein; GFAP, glial fibrillary acidic protein.
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